SNPMiner Trials: Mutation Report
Report for Mutation A581G
Developed by Shray Alag, 2019.
SNP Clinical Trial Gene
There are 2 clinical trials
Clinical Trials
Sulfadoxine-pyrimethamine (SP) is currently recommended by the World Health Organization for
use as intermittent preventive treatment against malaria in pregnancy (IPTp) in areas of
moderate to high malaria transmission. However, in some locales malaria parasites have lost
sensitivity to SP, compromising its protective effect. Dihydroartemisinin-piperaquine (DP) is
a candidate replacement for SP. This trial is designed to confirm the cardio-safety of DP
compared to SP amongst pregnant women in Tanzania.
NCT02909712 Malaria Pregnancy Cardiotoxicity Parasitemia Drug: sulfadoxine-pyrimethamine (SP) Drug: dihydroartemisinin-piperaquine (DHA-PQP)
Proportion of participants in Groups 1-4 with parasites that carry the A581G mutation and others biomarkers associated with SP resistance.. null. --- A581G ---
Polymerase chain reaction (PCR) methods will be used for genetic sequencing of molecular
markers (A581G) associated with malaria parasite drug resistance to SP. --- A581G ---
Primary Outcomes
Measure: Proportion of participants in Groups 3-4 with an absolute QTc of > 500 milliseconds
Time: Measured on day 7 post-dose
Secondary Outcomes
Measure: Proportion of participants in Groups 1-2 with an absolute QTc of > 500 milliseconds
Time: Measured on day 0
Measure: Proportion of participants in Groups 1-2 with an absolute QTc of > 480 milliseconds
Time: Measured on day 0
Measure: Proportion of participants in Groups 1-2 with an absolute QTc of > 460 milliseconds
Time: Measured on day 0
Measure: Proportion of participants in Groups 3-4 with an absolute QTc of > 500 milliseconds
Time: Measured on day 2
Measure: Proportion of participants in Groups 3-4 with an absolute QTc of > 480 milliseconds
Time: Measured on day 2
Measure: Proportion of participants in Groups 3-4 with an absolute QTc of > 450 milliseconds
Time: Measured on day 2
Measure: Incidence of participants in Groups 1-4 with QTcF prolongation > 500 milliseconds.
Time: Measured on days 0, 2 and 7
Measure: Incidence of participants in Groups 1-4 with QTcF deviation from baseline > 60 milliseconds
Time: Measured on days 0, 2 and 7
Measure: Incidence of participants in Groups 1-4 with ventricular arrhythmia captured on ECG recording and/or suspected by a clinical event as palpitation, dizziness, syncope, convulsion, or sudden death
Time: Measured on days 0, 2 and 7
Measure: Proportion of participants in Groups 1-4 with mean heart rate < 40 beats per minute
Time: Measured on days 0, 2 and 7
Measure: Proportion of participants in Groups 1-4 with mean heart rate > 130 beats per minute
Time: Measured on days 0, 2 and 7
Measure: Proportion of participants in Groups 1-4 with PR interval > 210 milliseconds
Time: Measured on days 0, 2 and 7
Measure: Proportion of participants in Groups 1-4 with PR interval > 220 milliseconds
Time: Measured on days 0, 2 and 7
Measure: Proportion of participants in Groups 1-4 with QRS interval > 110 milliseconds
Time: Measured on days 0, 2 and 7
Measure: Proportion of participants in Groups 1-4 with QRS interval > 120 milliseconds
Time: Measured on days 0, 2 and 7
Measure: Proportion of participants in Groups 1-4 with change in QTcF from baseline > 60 milliseconds + Absolute QTc > 480 milliseconds (QTcF refers to the QT interval that has been corrected using the Fridericia formula)
Time: Measured on days 2 and 7
Measure: Proportion of participants in Groups 1-4 with QTcF > 480 milliseconds and > 500 milliseconds (QTcF refers to the QT interval that has been corrected using the Fridericia formula)
Time: Measured on days 0, 2 and 7
Measure: Proportion of participants in Groups 3-4 with change in QTcF between day 0 pre-dose, day 2 post dose at peak > 60 milliseconds, and day 7 (QTcF refers to the QT interval that has been corrected using the Fridericia formula)
Time: Measured on days 0, 2 and 7
Measure: Proportion of participants in Groups 1-4 with arrhythmias
Time: Measured on days 0, 2 and 7
Measure: Incidence of participants in Groups 3-4 with sinus pause / arrest > 3.0 seconds
Time: Measured on days 0, 2 and 7
Measure: Incidence of participants in Groups 3-4 with 2nd degree atrioventricular block (Mobitz 2)
Time: Measured on days 0, 2 and 7
Measure: Incidence of participants in Groups 3-4 with 3rd degree atrioventricular block
Time: Measured on days 0, 2 and 7
Measure: Incidence of participants with ventricular tachycardia
Time: Measured on days 0, 2 and 7
Measure: Incidence of participants with torsades de pointes
Time: Measured on days 0, 2 and 7
Measure: Incidence of participants with ventricular fibrillation
Time: Measured on days 0, 2 and 7
Measure: Mean piperaquine absorption at maximum observed concentrations (Cmax) in Groups 3-4
Time: Measured on day 2
Measure: Incidence of participants who experience myocardial ischemia defined as: • ST-segment deviations ≥ 1 millimetre 80 millisecond after J-point, or • New Q-waves, or T-wave inversion
Time: Measured on days 0, 2 and 7
Measure: Incidence of participants who experience morphological changes of the T-wave
Time: Measured on days 0, 2 and 7
Measure: Incidence of participants who experience pathological U-wave
Time: Measured on days 0, 2 and 7
Measure: Incidence of participants who experience sinus pause or arrest > 3.0 seconds
Time: Measured on days 0, 2 and 7
Measure: Incidence of participants who experience 2nd degree atrioventricular block (Mobitz 2)
Time: Measured on days 0, 2 and 7
Measure: Incidence of participants who experience 3rd degree atrioventricular block
Time: Measured on days 0, 2 and 7
Measure: Incidence of participants who experience complete right bundle branch block
Time: Measured on days 0, 2 and 7
Measure: Incidence of participants who experience complete left bundle branch block
Time: Measured on days 0, 2 and 7
Measure: Proportion of participants in Groups 1-2 with and without parasitaemia at day 0 administered SP, who are aparasitaemic at day 7, day 14 and day 28, uncorrected and corrected by PCR methods
Time: Days 0, 7, 14, and 28
Measure: Proportion of participants in Groups 3-4 administered dihydroartemisinin‑piperaquine with and without parasitaemia at day 0, who are aparasitaemic at day 7, day 14 and day 28, uncorrected and corrected by PCR methods
Time: Days 0, 7, 14, and 28
Measure: Proportion of participants in Groups 1-4 with parasites that carry the
A581G mutation and others biomarkers associated with SP resistance.
Time: Day 0
In Afghanistan, studies over the past 15 years have shown a high degree of Plasmodium
falciparum resistance to chloroquine. In 2003 the high failure rate of chloroquine against
falciparum malaria led the national malaria treatment programme to switch its recommended
first line drug treatment for uncomplicated Plasmodium falciparum malaria to
artemisinin-based combination therapy (ACT) in the form of
Artesunate/Sulphadoxine-Pyrimethamine (AS+SP). Second line drug treatment is oral quinine (7
days).
For operational reasons, prior to recent studies (manuscript in preparation) there have been
no molecular data on P. falciparum SP resistance markers from within the borders of
Afghanistan. These studies have revealed early evidence of increasing SP resistance
(resistance polymorphisms with double DHFR & triple DHPS mutations). The aim of this study is
to conduct a focused, prospective study in Kunar for monitoring of the efficacy of the AS+SP
combination in this province, along with molecular studies of isolates from recruited
patients.
NCT01707199 Uncomplicated P. Falciparum Malaria Drug: Artesunate + Sulphadoxine-pyrimethamine
However the investigators have obtained recent (submitted)
data showing that in addition to two resistance polymorphisms in DHFR (C59R and S108N) that
are well known to be at high frequency in the region, a small number of parasites in the
Kunar province have three mutations (A437G, K540E and A581G) in DHPS. --- C59R --- --- S108N --- --- A437G --- --- K540E --- --- A581G ---
Primary Outcomes
Description: WHO defined ACPR
Measure: Adequate clinical and parasitological response (ACPR)
Time: 42 days
Secondary Outcomes
Description: The incidence of any adverse event will be documented. All patients will be asked routinely about previous symptoms and about symptoms that have emerged since the previous follow-up visit.
Measure: Adverse events
Time: 42 days
Description: To study polymorphisms in PfDHFR, PfDHPS and copy number of PfGCH1 which are considered as markers of resistance to Sulphadoxine-pyrimethamine (SP) components.
Measure: Molecular markers for antimalarial drug resistance
Time: Baseline
HPO Nodes